from jules: There are many exciting stories coming out of this EAL in Amsterdam that just finished on sunday, I landed back here in NYC after an 8-hour flight to finish up reporting coverage after filing many live real-time reports from EASL. About 25-30 reports are already posted on the NATAP website, but there are a lot of more studies & results to report to you over the next week or so & more analyses like this one, here is link to posted EAL reports, but read this interesting story below.....

This is the first study treating boceprevir or telaprevir failures with a new therapy, NS5A BMS052 Daclatasvir+ nucleotide GS7977 Sofosbuvir. And the SVR rate is 100%. 41 genotype 1 patients received BMS052+GS7977 once a day, 20 without RBV & 21 with RBV, treatment was for 24 weeks, there was 1 patient who did not come in for post-treatment week 12 but did come back at week 24 post-treatment & was undetectable, so officially they called it 95% SVR. 80% of the patients had at least F2 stage of disease, meaning they had some moderate stage of disease progression, & I spoke with the study investigator who presented the data in an oral session at EASL Mark Sulkowski, who said that many of the patients may have had more advanced disease, even some may have had cirrhosis. These results are of course very encouraging for patients who did not achieve an SVR with the triple therapy of boceprevir or telaprevir + peg/Rbv. The 2 oral drugs used in this study to treat these patients were BMS052, a potent once daily NS5A & GS7977 a potent once daily nucleotide, so both these drugs are from different classes than boceprevir & telaprevir which are protease inhibitors, this is likely a key element to success of the regimen because if a patient fails & develops drug resistance to which a patient often does if they do not achieve an SVR with a protease triple regimen, then retreatment with a protease inhibitor may not be fully active, this is and has bone a bone of contention, that is, some researchers have presented several studies over the past 2 years that if a patient fails a protease triple regimen & develops mutations after 1-3 years these mutations disappear & that patient should be able to be retreated with a protease inhibitor & achieve a potent response & that the previous mutations that developed disappeared & would not prevent re-use. Well, if you look at the slide in the presentation by clicking this link there were lots of protease inhibitor mutations they saw at baseline before these patients were retreated & at the oral presentation Sulkowski said at the mic in response to a question from the audience that these patients had stopped their previous therapy 1-2 or more years ago, so he was suggesting that these mutations do not disappear & if a patient were retreated with a PI perhaps it would not be successful. This goes against strong arguments that those other researchers were saying regarding that the protease resistance mutations would disappear, this could be a very important issue. So, if this is true for protease inhibitors & for NS5A inhibitors and for non nucs, that mutations do not disappear, then we might need 2nd generation NS5A & protease inhibitors, and there are several in development. As well, this raises a concern that deciding to start treatment is an important decision not to take lightly, it requires selecting a regimen that fits your situation. So if a patient is in a harder to treat situation, like a prior null cirrhotic, pick a regimen that you feel confident can successfully suppress HCV virus replication so you won't get resistance mutations, and adherence is very important. A patient must be totally adherent, not miss doses, and follow instructions closely like if there is a food requirement make sure this is followed. Merck's MK5172, Achillion's NS5A, and GS5816 is a new 2nd generation NS5A from Gilead, preclinical data was presented in 2 posters at EASL. These drugs might become important for this situation. Another relevant point is regarding the nucleotide class of drugs, that is GS-7977 & VX135, which is in phase 2 clinical study development. It is hard to develop resistance to this class, in studies so far by Gilead it is unusual if not at all that they see resistance, and in the QUANTUM Study reported here at EASL they retreated patients who did not achieve SVR with GS-7977 & 76-85% achieved SVR suggesting retreatment with GS-7977 for patients is possible & may be very useful, see link below to read QUANTUM Study. Another point, at EASL April 2012, link to study below, the same 2 drug combination of BMS052+GS7977 received a lot of fanfare because in this small phase 2 study of about 90 patients who received just 12 weeks of therapy 100% of Gt1 patients & 91% (40/44) with Gt2 or 3 achieved SVR, read the article with the link below to see what happened to these 4 Gt2/3 patients who did not achieve SVR. And then read the followup to this study presented at AASLD in November 2012 where they reported 93% SVR for Gt2/3 and 95-100% SVR depending on whether therapy was 12 or 24 weeks, but again read the link below to see what happened to the patients in the study who did not achieve SVR. At EASL GT3 patients did not respond as well to GS-7977+Rbv compared to GT2 or Gt1, IDX719 is a NS5A with Gt3 activity in clinical development, see link below, GS5816 is in preclinical showing GT3 activity & PPI-383 is a non nuc also with GT3 activity in pre-clinical development.